Type 2 diabetes mellitus is a disease characterized by insulin secretion failure from pancreatic β cells and a decrease in insulin sensitivity of tissues including liver, adipose tissue and muscle. Various diabetes remedies have been developed that promote the secretion of insulin from pancreatic β cells and have a drug effect of improving insulin sensitivity in tissues. As an insulin secretion promoter, sulfonylurea (SU agent), gilded drug, incretions related drug, and the like are clinically applied as a therapeutic agent for type 2 diabetes accompanied by insulin secretion failure (Non-Patent Document 1). Of these, sulfonylureas are most widely used.
An ATP-sensitive potassium channel (KATP channel) is expressed in pancreatic β-cells. The KATP channel is composed of Kir6.2 which is a hole forming subunit, and SUR1 which is a control subunit (Non-Patent Documents 2 to 4). SUR1 is also a receptor for sulfonyl urea and glinide drugs.
Sulfonylureas and glinide drugs close the KATP channel by binding to SUR1. As a result, the pancreatic β-cell membrane is depolarized, the voltage-dependent calcium channels (VDCCs) are released, the calcium ions flow, the calcium ion concentration in the pancreatic β cells rises, and insulin secretion is induced (Non-Patent Documents 5 to 8).
In addition to the function of closing the KATP channel, sulfonylurea also has the function of directly activating Epac2A/Rap1 which is a signal molecule stimulating insulin secretion in pancreatic β cells (Non-Patent Documents 9 and 10, Patent Document 1). Activation of Epac2A by sulfonylurea is caused by cooperation of sulfonylurea and cAMP (Non-Patent Document 11).
Sulfonylureas and glinide drugs are widely used as therapeutic agents for type 2 diabetes. However, while these agents have a therapeutic effect of promoting the secretion of insulin, they may cause persistent hypoglycemia as a side effect. It is believed that the cause is that since these agents are stable in vivo, their action is sustained for a long time (Non-Patent Document 12). The side effect tends to occur particularly in elderly people and patients with renal failure, among diabetic patients. Therefore, there is a clinical need for new drugs of type 2 diabetes drugs, which have a low incidence of side effects such as hypoglycemia.